The long range objectives of this laboratory are to determine the mechanisms by which enzymes catalyze reaction, and in a more general way to determine the nature of biological interactions at the molecular level. To these we have now added an attempt to gain some understanding of the energetics of such interactions. For some years we have focussed our investigations on the glutamic dehydrogenase system which offers a wide variety of phenomenon with which to pursue such studies. One important phase of this work is practically completed: we now feel that we have a good working knowledge of most of the complexes formed between the enzyme and its various reactants, products, modifiers, and coenzymes, the connectivities of the ligands in those complexes, their stoichiometries, physical and optical properties, modes of interconversion, and their place in the kinetic time course of the reaction. We are now ready to begin an intensive investigation into the detailed chemical events that occur in catalysis and into the roles that the various functional groups on the enzyme play in those interconversions. To achieve those new goals we are going to need some new investigative approaches. A number of these new tools, their state of development, applicability to our problems, and some preliminary results with them, are described in the proposal that follows.